RS49836B - PROCEDURES AND INTERMEDIATES FOR OBTAINING ANTI-CANCIN UNITS - Google Patents

Abstract

A process for the preparation of a compound of Formula I: or a pharmaceutically acceptable salt or solvate thereof wherein: R 1 and R 2 are each independently selected from C 1 -C 10 alkyl and C 1 -C 10 alkoxy, wherein said alkyl and alkoxy are optionally substituted with up to two substituents independently selected from hydroxy and C1C6alkoxy; R 15 is H, C 1 -C 10 alkyl or - (CH 2) q (C 6 -C 10 aryl), wherein q is a number from 0 to 4; comprising reacting a compound of Formula 2: wherein R 15, R 1 and R 2 are as previously defined and G is a blocking group-C (OH) R 3 R 4; R3 and R4 are each independently C1-C6alkyl; with an alkali metal or alkali metal hydroxide in a solvent comprising hydroxy substituted C1-C10alkyl.

Description

State of the art

The subject invention relates to methods and intermediates for obtaining compounds that are applicable in the treatment of hyper-proliferative disorders, such as cancers, in mammals.

United States Patent 5,747,498, issued May 5, 1998, which is incorporated herein by reference in its entirety, relates to a new series of Mnazoline derivatives including (6,7-bis(2-methoxyethoxyethoxy)hydrochloride, which are inhibitors of the erbB family of oncogenic and proto-oncogenic protein tyrosine kinases, such as the epidermal growth factor receptor (EGPR) and therefore are useful in the treatment of proliferative disorders, such as human cancers, United States Provisional Patent Application entitled <M>N>(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate anhydrate and monohydrate" dated April 29, 1998 under the names of inventors T. Norris, D. Santafianos, DJ. M. Allen, R. M. Shanker and J. W. Raggon, Deputy PC 10074, which is incorporated herein by reference, relates to N-(3-ethynylphentermino)^ forms having the same anti-cavity properties as the corresponding hydrochloride salt as given above. The subject invention relates to processes and intermediates for obtaining anti-cancer compounds that are not disclosed in the US patent and patent application cited above.

Summary of the invention

The present invention relates to a process for obtaining compounds of the formula

and pharmaceutically acceptable salts and salts of the mentioned compounds, where:

R' and R<1> are each independently selected from C1-C10 alkyl and C1-C10 alkoxy wherein said alkyl and alkoxy are optionally substituted with up to two substituents independently selected from hydroxy and C1-C6 alkoxy;

R<15> is H, C1-C10alkyl, or -(CH2)q(C6-C10aryl), where q is an integer from 0 to 4;

which includes treating compounds of formula £:

wherein R<1S>, R<1> and R<2> are as defined above, and G is a blocking group selected from -C(OH)R<3>R<4> and -SiR<J>R<4>R<5>;

R}, R<*> and R<5> are each independently C,-C,0alkyl, either with (a) an alkali metal or alkaline earth metal hydroxide in a solvent comprising a hydroxy-substituted C,-C,0alkyl wherein G is -C(OH)R<J>R<4>or with (b) a tetra-(C,-C6alkyl)-ammonium fluoride compound in an aprotic solvent wherein G is -SiR<3>R<4>R<5>, ;In a preferred embodiment, where G is -C(OH)R<3>R<4>, said solvent is a secondary alcohol, such as butan-2-ol or isopropanol, and said alkali metal or alkaline earth metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide, most preferably is sodium hydroxide. In another preferred embodiment, where G is -SiR<3>R4R5, said tetra-(C,-C6alkyl)-ammonium fluoride compound is tetra-(n-butyl)-ammonium fluoride and said aprotic solvent is selected from tetrahydrofuran (THF), diethyl ether, dimethoxyethane (DME), toluene, dichloromethane, chloroform and two or more of the foregoing solvent and most preferably THF. The present invention also relates to the preparation of a compound of formula 2, as described above, which comprises treating a compound of formula 3, where R<1> and R<1> are as defined above, with a compound of formula 4; where G and R<15> are as defined for said compound of formula 2L; In a preferred embodiment of the above process, a compound of formula 3 is treated with a compound of formula 4 in an organic a solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), THF, acetonitrile (MeCN) or a mixture of two or more of the foregoing solvents, and most preferably acetonitrile. The subject invention also relates to a process for obtaining a compound of formula 3, as defined above, which includes treating a compound of formula 5; ;with thionyl chloride in anhydrous dichloromethane. In a preferred embodiment of each of the above reactions described above, R<1> and R<2> are both 2-methoxyethoxy and R1 is H. The present invention also relates to the preparation of compounds of formulas 6 and 2; and pharmaceutically acceptable salts and solvates thereof, wherein R<15> is as defined above, R<6> is (CrCl0alkyl) or -(CH2)mO(CH2)nCH3; ;R<7>is (CrC10alkyl) or (C1-C6alkyl)(C6-C10aryl) where the above R<7>groups are optionally substituted with 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, trifluoromethoxy, (CrC6alkyl)sulfonyl, CrC6 alkyl, CrC6alkoxy, C6-C10aryloxy and C 6 -C 10 arylsulfonyl; ;each m is independently an integer from 1 to 6, and n is an integer from 0 to 3; ;which includes treating the compound of formula 8; ;wherein G<1>is -C(OH)R<3>R<4>aR1S,R6, R<3>and R<4>are as defined above, with a primary or secondary alcohol of the formula R<7->OH where R<7>is as defined above, in the presence of an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, and sodium hydroxide is most preferred. In a preferred embodiment of the above reaction, R<6> is 2-methoxyethoxy and said alcohol of the formula R<7->OH is preferably a secondary alcohol. The present invention also relates to a process for obtaining compounds of the formula; and pharmaceutically acceptable salts and solvates thereof, wherein R<15>, R<ć> and R<7> are as defined above; R<8>, R<9> and R<10> are each independently selected from H, C,-C10alkyl, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -OR11, -C(0)R<n>, -C(0)OR<u>, -NR<2>C(0)OR<14>, -(0)C(O)R'\ -NR<12>S02R<14>, -S02NR<H>R<12>, -NR<12>C(0)R<n>, -C(0)NR<u>R<12>, -NRnR<12>, -S(<O>)j(CH2)q(C6-C10aryl), -S(0)j(CrC6 alkyl), where j is an integer from 0 to 2, -(CH2)q(C6-C10aryl), -O(CH2)q(C6-C10aryl), -NR,<2>(CH2)q(C6-C10aryl), and -(CH2)q(4-10 Member Heterocycle) where q is an integer from 0 to 4; said alkyl group optionally contains one or two hetero moieties selected from O, -S(0)j- where j is an integer from 0 to 2, and -N(R<12>)- provided that two O atoms, two S atoms or O and an S atom are not attached directly to each other; said aryl and heterocyclic groups are optionally fused to a C6-C10aryl group, a C5-C8 saturated cyclic group or a 4-10 membered heterocyclic group; and said alkyl, aryl and heterocyclic groups are optionally substituted with 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR<12>S02R<14>, -S02NR<ll>R<12>, -C(0)R<H>, -C(0)OR<11>, -OC(0)R<u>, -NR<12>C(0)OR'<4>, -NR,<2>C(0)R<n>, -C(0)NR<n>R<12>, -NR<n>R<12>, -OR", C,-C10alkyl, -(CH2)q(C6-C10aryl), and -(CH2)q(4-10 membered heterocycle), where q is an integer going from 1 to 4; each R" is independently chosen between H, C1-C10alkyl, -(CH2)q(C6-C10aryl) and -(CH2)q(4-10 membered heterocycle), where q is an integer ranging from 0 to 4; said alkyl group optionally includes 1 or 2 hetero moieties selected from 0, -S(0)j- where j is an integer from 0 to 2 and -N(R<12>)- provided that two O atoms, two S atoms or an O and an S atom are not directly bonded to each other; said aryl and heterocyclic R groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group or a 4-10 membered heterocyclic group; and the above R11 substituents, except hydrogen, are optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -C(0)R<12>, -C(0)OR1<2>, -OC(0)R1<2>, -NR<12>C(0)R<13>, -C(O)NR<12>R<13>, -NR12R<13>, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; each R12 and R<13> is independently H or C1-C6 alkyl, and R<14> is selected from the substituents included in the definition of R<u> with the exception that R<14> is not H; ; which includes treating the compound of formula 10 ; where R<15>, R<6>, R<8>, R<9> and R<10> are as defined above, with a primary or secondary alcohol of the formula R<7>OH where R<7> is as defined above, preferably a primary alcohol, in the presence of an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, sodium hydroxide is most preferred. The above compounds of formula L. 6*7 and 2 are applicable in the treatment of hyper-proliferative disorders, such as mammalian cancers.

The present invention also relates to intermediates of formula 2 as described above with respect to the preparation of compounds of formula I,

The term "halo" as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. Preferred groups are fluoro, chloro and bromo.

The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having branched or cyclic moieties, or a combination of the above groups. It is understood that for the said alkyl group in order to include cyclic groups at least three carbon atoms are required in said alkyl group.

The term "aryl" as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by hydrogen removal, such as phenyl or naphthyl.

The term "4-10 membered heterocycle" as used herein, unless otherwise noted, includes aromatic or non-aromatic groups containing one or more heteroatoms each selected from O, S, and N wherein each heterocyclic group has from 4-10 atoms in its ring system. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least five atoms in their ring system. Heterocyclic groups include benzo-fused ring systems that are substituted with one or more groups. An example of a 4-membered heterocyclic group is azetidinyl (which is derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolonyl, quinoxalinyl, naphthyridinyl and furopyridinyl. The above groups, as derived from the compounds listed above, may be C-attached or N-attached where possible. For example, a group derived from pyrrole can be pyrrole-1-yl(N-attached) or pyrrole-3-yl(C-attached).

The phrase "pharmaceutically acceptable salts" as used herein, unless otherwise indicated, includes salts of acid or base groups that may be present in a compound of the present invention. The compounds obtained according to the present invention, those which are basic in nature, can form a wide variety of salts with various inorganic or organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such base compounds are those which form non-toxic acid addition salts, for example, salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [eg, 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) salts.

Compounds obtained according to the present invention which include a basic group, such as an amino group, can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.

Those compounds of the present invention which are acidic in nature can form base salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, especially calcium, magnesium, sodium and potassium, of the compounds of the present invention.

The compounds obtained according to the present invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. This invention relates to the optical isomers and stereoisomers of the compounds obtained according to the present invention and to their mixtures. Compounds of formula 1 may also exist as tautomers. The present invention relates to the use of all such tautomers and mixtures thereof.

The subject of the invention also includes isotopically labeled compounds obtained according to the present invention, and their pharmaceutically acceptable salts, which are identical to those expressed in formula 1, but due to the fact that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as<2>H,<3>H,<1>3C, I4C,<15>N, "O, "O,<3>SS, ,<8>F, and<36>C1, in the same order. The compounds obtained according to the present invention, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example, those in which radioactive isotopes such as<3>H and 14C are incorporated, are applicable in drug and/or substrate tissue distribution assays. Tritium, i.e. <3>H and carbon 14, i.e. UC, are isotopes particularly preferred due to their ease of preparation and detectability. Furthermore, substitution with heavier isotopes, such as deuterium, i.e. 2H, may provide certain therapeutic advantages resulting from their greater metabolic stability, for example increased half-life or reduced dosage requirements may be desirable in some cases. Isotopically labeled compounds of formula 1 of the present invention and their prodrugs can usually be obtained according to the procedures described in the Schemes and/or Examples and Preparations below, by substituting a readily available isotopoxy labeled reagent for a non-isotopically labeled reagent.

Detailed description of the invention

The processes of the present invention may be described with reference to Schemes 1-3 given above. In the reactions described below, all reactions are carried out at atmospheric pressure and room temperature (about 20-25°C) unless other conditions are specified. Further, unless otherwise stated, the substituents R'-R10,R15, G and G<1> are as described above.

In Scheme 1, compounds of formula 1 can be obtained by first treating the starting compound of formula 5, which can be obtained according to methods known to those skilled in the art, with thionyl chloride in anhydrous dichloromethane at reflux temperature (about 38-42°C at atmospheric pressure) to give a compound of formula 3. A compound of formula 2 can be obtained by treating a compound of formula 3 with a compound of formula 4 in an organic solvent such as is DMF, DMSO, THF, MeCN or a mixture of two or more of the above solvents, preferably MeCN, at a temperature ranging from 50°C to reflux, preferably reflux. The above acronyms are as defined in the pronatasco brief hereafter. A compound of formula i can be obtained by treating a compound of formula 2 with an alkali metal or alkaline earth metal hydroxide in a solvent comprising C,-C,0alkyl substituted with at least one hydroxy group where G is -C(OH)R<3>R<4> or with a tetra-(C!-C6alkyl)-ammonium fluoride compound in an aprotic solvent where G is -SiR<3>R<4>R<5>. Where G is -C(OH)R<3>R<4>, the solvent is preferably a secondary alcohol, such as butan-2-ol or isopropanol, said alkali metal or alkaline earth metal hydroxide may be selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide, preferably sodium hydroxide, and the reaction is preferably carried out at a temperature ranging from about 100°C to about 150°C. Where G is -SiR<3>R<4>R<s>, the tetra-(CrC6 alkyl)-ammonium fluoride compound is preferably tetra-(n-butyl)-ammonium fluoride, the aprotic solvent may be selected from THF, diethyl ether, DME, toluene, dichloromethane, chloroform and a mixture of two or more of the foregoing solvents, preferably THF, and the reaction is preferably carried out at a temperature ranging from about room temperature to about 70°C. The anti-cancer compounds of formula I can be converted into pharmaceutically acceptable salts as described below.

In Scheme 2, the anti-cancer compounds of formulas 6 and 7 can be obtained by treating an intermediate of formula 8 with a primary or secondary alcohol of formula R<7>OH, where R<7> is as defined above, in the presence of an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, preferably sodium hydroxide, at a temperature ranging from about 100°C to about 150°C. Use of a secondary alcohol of formula R<7->OH will minimize conversion to the asymmetric analog of formula 2, while use of a primary alcohol of formula R<7->OH will increase the relative concentration of the asymmetric analog of formula 2- Thus, depending on the analog that is desired, a secondary or primary alcohol may be preferred. Compounds of formula 6 and 7 can be separated by a variety of methods, such as chromatography, known to those skilled in the art. Compounds of formulas 6 and 7 may be converted into pharmaceutically acceptable salts as described hereinbelow.

In Scheme 3, compounds of formula 9 can be prepared by treating a compound of formula 10 with a primary or secondary alcohol of formula R<7->OH as described above with respect to Scheme 2. Since the goal of the reaction of Scheme 3 is to obtain an asymmetric analog, the use of a primary alcohol of formula R<7->OH is preferred. Compounds of formula 9 may be converted into pharmaceutically acceptable salts as described hereinbelow.

Certain compounds obtained according to the process of the present invention listed above may have asymmetric carbon atoms. Compounds having a mixture of isomers at one or the other center will exist as diastereomeric mixtures, which can be resolved into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, for example, by chromatography or fractional crystallization. All such isomers, including diastereomeric mixtures, are considered part of the present invention.

The compounds listed above which are basic in nature can form a wide variety of different salts with various inorganic and organic acids. Although such salts may be pharmaceutically acceptable for use in mammals, it is often desirable in practice to initially isolate the compounds of the present invention from the reaction mixture in the form of a pharmaceutically unacceptable salt and then convert this back into the free base form by treatment with an alkaline reagent and then convert this free base back into a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of this invention are readily obtained by treating the base compound with a substantially equivalent amount of a selected mineral or organic acid in an aqueous solvent or in a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid acid salt can also be precipitated from a solution of the free base in an organic solvent by addition of a suitable mineral or organic acid.

Those compounds given above which are acidic in nature can form base salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, in particular, sodium and potassium salts. These salts are obtained by conventional techniques. Chemical bases that are applicable as reagents for obtaining pharmaceutically acceptable base salts are those that form non-toxic base salts with the acid compounds of the present invention. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium, magnesium, etc. These salts can be easily obtained by treating the corresponding acid compounds with an aqueous solution containing the desired alkali metal alkoxide or hydroxide, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, these salts can be prepared by mixing lower alkanol solutions of the acid compounds and the desired alkali metal alkoxide or hydroxide together and then evaporating the resulting solution to dryness in the same manner as before. In both cases, stoichiometric amounts of reagents are preferably used in order to ensure completion of the reaction and to ensure maximum yields of the desired final product.

The examples given below are further provided as examples of the processes and intermediates of the subject invention, although it should be understood that the scope of the subject invention is not limited by the following examples.

Example1

Preparation of 3-[(Crimethylsilyl)ethynyl]nitrobenzene

A mixture of 1-bromo-3-nitrobenzene (10.0 g, 49.45 mmol) and trimethylsilylacetylene (8.4 ml, 59.34 mmol) was treated with triethylamine (33 ml) to give a small amount of white precipitate. Obtained

the mixture is treated with dichlorobis(triphenylphosphono)palladium II (7 mgg, 0.01 mmol) and copper(I) iodide (8.5 mg, 0.04 mmol) and heated to 80-85°C (oil bath temperature) for 4 hours. The resulting pale yellow mixture was allowed to cool to room temperature and the solid was removed by filtration with triethylamine (33 mL). The light yellow solution was concentrated by evaporation and dried under vacuum at room temperature overnight to give the title product (11.11 g, 102%) as a brown oil. gc/mass spectroscopy showed the final compound to be 100% pure; m/e 219 (M+H)<+>.

Example 2

Preparation of 3-[(trimethylsilyl)ethynyl]aniline

A mixture of the nitro compound, 3-[(trimethylsilyl)ethynyl]nitrobenzene obtained as described above (0.86 g, 3.92 mmol) in 2-propanol (30 mL) was degassed with nitrogen and treated with 5% palladium on alumina (268 mg). The shaker was mixed under a hydrogen atmosphere (30 psig) on a Parr shaker for 22 hours. The reaction mixture was filtered through a pad of Celite™ (diatomaceous earth) and concentrated by evaporation to give an oil which was dried under vacuum overnight to give the title product (692 mg, 93%) as a tan oil.

6H(300 MHz; CDCl3) 0.24(9H, s), 3.56(2H, bs), 6.62(1H, ddd, J=1.0, 2.3 & 8.0), 6.78(1H, t, J=2.2), 6.87(1H, dt, J=7.7&1.2), 7.07(1H, t, J=7.8); dc(75.5 MHz; CDC13) 93.4, 105.4, 115.6, 118.2, 122.4, 123.8, 129.2, 146.2; m/e 190(M+H)<+>.

Example 3

Preparation of 6, 7-bis(2-methoxyethoxy)-N-[3-[(trimethylsilyl)ethynyl]phenyl]-4-quinazolinamine, monohydrochloride

4-Chloro-6,7-bis(2-methoxyethoxy)quinazoline (942 mg, 3.01 mmol) was treated with a solution of aniline (645 mg, 3.41 mmol) in 2-propanol (14 mL) and heated at reflux for 2.5 hours. The mixture is allowed to cool to room temperature and stirred for 1 hour. The solid was collected by filtration, washed with 2-propanol (5 mL) and dried under vacuum overnight to afford the title product (1.33 g, 88%) as a white solid.

5H(400 MHz; CDCl3) 0.21(9H, s), 3.38(3H, s), 3.41(3H, s), 3.72(2H, m), 3.77(2H, m), 4.10(2H, s), 4.53(2H, s), 7.20(1H, t, J=7.8), 7.23-7.28(2H, m), 7.75(1H, d, J=7.8), 7.88(1H,

s); 8.20(1H, s), 8.42(1H, s); m/e 466(M+H)+.

Example 4

Preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, monohydrochloride

A suspension of the silyl compound, 6,7-bis(2-methoxyethoxy)-N-[3-[(trimette monohydrochloride) obtained above (1.22 g, 2.43 mmol) in tetrahydrofuran (6.1 mL) was treated with a 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (2.6 mL, 2.55 mmol) and stirred at room temperature for one hour. 2-propanol (12.2 ml) and concentrated by evaporation. The oil in 2-propanol (20 ml) was treated with concentrated hydrochloric acid (0.2 ml) to give a precipitate. The solid was collected by filtration, washed with 2-propanol (2 ml) and dried in vacuo to give the title product (747 mg, 73%). colorless solids (tt 226-229°C).

5H(300 MHz; d6-DMSO) 3.36(6H, s), 3.77-3.80(4H, m), 4.30(1H, s), 7.39(1H, s), 7.41(1H, d, J=7.8), 7.50(1H, t, J=7.9), 7.79(1H, d, J = 8.1), 7.88(1H, s); 8.40(1H, s), 8.86(1H, s), 11.48(1H, bs); <5C (100 MHz; d6-DMSO) 58.4, 58.5, 68.7, 69.2, 69.7, 67.0, 81.3, 83.0, 100.3, 105.2, 107.2, 121.9, 125.4, 127.6, 128.9, 129.2, 135.2, 137.7, 148.3, 149.2, 155.4, 158.0; m/e 394(M+H)<+>.

Example 5

Obtaining 4-[ 3-[[ 6, 7- bis( 2- methoxyethoxy]- 4- quinazolintt] amino] phenyl]- 2- methyl

3-butyn-2-ol, monohydrochloride

4-Chloro-6,7-bis(2-methoxyethoxy)quinazoline (15 g, 48 mmol), 4-(3-aminophenyl)-2-methyl-3-butyn-2-ol (9.2 g, 52.8 mmol) and acetonitrile (225 mL) were heated at reflux for five hours. The mixture is cooled to 5-10°C and stirred for one hour. The solid was collected by filtration, washed with acetonitrile (15 mL) and dried under vacuum overnight to afford the title product (23.4 g, 100%) as a white solid.

SH(400 MHz; d6-DMSO) 1.44(6H, s), 3.31-3.32(6H, m), 3.69-3.75(4H, m), 4.24-4.30(2H, m), 4.35-4.37(2H, m), 7.25(1H, m), 7.39(2H, m), 7.72-7.74(2H, mjijio, 8.47(1H, s), 8.79(1H, s), 11.64(1H, s); m/e 452(M+H)<+.>

Example 6

Obtaining 4-[3-[[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]aminoJphenyl]-2~methyl

3- butyne-2-ol

The 4-[3-[[6,7-bis(2-methoxyethoxy]-4-hyiazolinyl]am obtained before (19.0 g, 39.7 mmol), water (95 mL) and ethyl acetate (380 mL) were stirred together at room temperature to build up the mixture. The pH of the mixture was adjusted to pH 10-12 with 50% aqueous sodium hydroxide to give two clear layers. The organic layer was separated from aqueous layer and concentrated under vacuum to a volume of approximately 190 ml. After a period of granulation in an ice bath, crystals of the title compound were formed, filtered and dried to give the product (15.13 g, 86%).

aH(400 MHz; CDCl3) 1.56(6H, s), 3.35(3H, s), 3.37(3H, s), 3.7-3.71(4H, m), 4.13-4.19(4H, m), 7.0(1H, m), 7.13-7.17(2H, m), 7.3(1H, m), 7.6(2H, m), 8.55(1H, s); m/e 452(M-fH) + .

Example 7

Preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, monohydrochloride

4-[3-[[6,7-bis(2-methoxyethoxy]-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol, monohydrochloride which was obtained as described above (32.34 g, 66.3 mmol), water (300 ml) and butan-l-ol (600 ml) were stirred together at room temperature to build up the mixture. The pH of the mixture was adjusted to pH 10-12 with 50% aqueous sodium hydroxide to give two clear layers. The organic layer is separated from the aqueous layer and the water is azeotropically removed from the butan-l-ol solution. Anhydrous sodium hydroxide (0.13 g, 3.3 mmol) is added to the butan-l-ol solution. solution and the resulting mixture is heated under reflux at 115-120°C for 24 hours. Butan-1-ol (150 mL) was removed by distillation and the concentrated reaction mixture was cooled to 15-25°C. Concentrated hydrochloric acid (66.1 ml) and butan-l-ol (60 ml) were added to the cooled concentrate and the mixture was granulated overnight at 20-25°C to effect crystallization. Crystals of the title product were isolated by filtration and dried under vacuum at 45-50°C to remove butan-l-ol. Yield (21.0 g, 73.3%). Purity according to HPLC: 96.5%.

Example 8

Obtaining N-(3-ethynylphenyl)-6,7-bis(2-methoMethoctyl)-4-quinazolinamine,

methanesulfonic acid salts

4-[3-[[6,7-bis(2-methoxyethoxy]-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol, monohydrochloride which was obtained as described above (32.34 g, 66.3 mmol), water (300 ml) and butan-l-ol (600 ml) were stirred together at room temperature to build up the mixture. The pH of the mixture was adjusted to pH 10-12 with 50% aqueous sodium hydroxide to obtain two clear layers. The organic layer is separated from the conducting layer and the water is azeotropically removed from the butan-l-ol solution. Anhydrous sodium hydroxide (0.13 g, 3.3 mmol) is added to the solution

azeotropically dried butan-1-ol solution and the resulting mixture is heated under reflux at 115-120°C for 24 hours. The reaction mixture was cooled to 15-25°C and methanesulfonic acid (4.6 ml) was added and the mixture was granulated overnight at 20-25°C for crystallization. Crystals of the title product were isolated by filtration, washed with butan-l-ol (25 ml) and dried under vacuum at 45-50°C to remove butan-l-ol. Yield (29.16 g, 90%). Purity according to HPLC: 96.7%.

Example 9

Obtaining N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,

monohydrochloride

4-[3-[[6,7-bis(2-methoxyethoxy]-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol, obtained as described above (20.0 g, 44.3 mmol), anhydrous solid sodium hydroxide (0.09 g, 2.2 mmol) and butan-2-ol (400 mL) were mixed together and heated under reflux at 100-102 °C for 36 hours. The reaction mixture is cooled to 15-25 °C and concentrated hydrochloric acid (4.1 ml) is added. The resulting mixture is granulated overnight at 20-25 °C. The crystals of the title product are isolated by filtration, washed with butan-2-ol (25 ml) and dried under vacuum. of butan-2-ol removal (17.7 g, 93%). Purity according to HPLC: 99.1%.

Example 10

Obtaining N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,

monohydrochloride

4-[3-[[6,7-bis(2-methoxyethoxy]-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol, which was prepared as described above (20.0 g, 44.3 mmol), anhydrous solid sodium hydroxide (260 mg, 6.5 mmol) and butan-2-ol (200 mL) were mixed together and heated in a pressure vessel at 135-140°C for 23 hours. The reaction mixture is cooled to 60-65°C. The resulting mixture is granulated overnight at 20-25°C. The mixture is treated with water (10 ml) and stirred at 58-60°C for 21 hours. two hours. Crystals of the title product is isolated by filtration, washed with propan-2-ol (2 x 30 ml) and dried under vacuum at 45-50°C to remove propan-2-ol. Yield (17.6 g, 92%).

Example 11

Obtaining N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,

monohydrochloride

4-[3-[[6,7-bis(2-methoxyethoxy]-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol, which is white as

as described above (5.0 g, 11 mmol), anhydrous solid sodium hydroxide (44 mg, 11 mmol) and 2-methoxyethanol (50 mL) were mixed together and heated at reflux for 47 h. The reaction mixture was cooled to 20-25°C and concentrated hydrochloric acid (1.1 ml) was added. The resulting mixture is granulated at 20-25°C for one hour for crystallization. Crystals of the title product were isolated by filtration, washed with 2-methoxyethanol (10 ml) and dried under vacuum at 45-50°C to remove 2-methoxyethanol. Yield (3.73 g, 78%).

Example 12

Obtaining N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,

methanesulfonic acid salt

4-[3-[[6,7-bis(2-methoxyethoxy]-4-quinazolinylamino]phenyl]-2-methyl-3-butyn-2-ol, obtained as described above (20.0 g, 44.3 mmol), anhydrous solid sodium hydroxide (0.09 g, 2.2 mmol) and butan-2-ol (400 mL) were mixed together and heated at reflux at 100-102° C. for 36 hours. The reaction mixture was cooled to 15-25° C. and methanesulfonic acid (5.1 g, 53.2 mmol) was added. The resulting mixture was granulated at 20-25° C. for 1 hour. The title product crystals were isolated by filtration, washed with butan-2-ol (25 ml) and dried under vacuum. 45-50°C for removal butan-2-ol. Yield (19.45 g, 90%). Purity according to HPLC 98.5%.

Example 13

Preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazotinamine

4-Moro-6,7-bis(2-methoxyethoxy)quinazoline (50g, 160mmol), 3-ethylaniline (21.34g, 176mmol) and propan-2-ol (500ml) were heated at 78-82°C for 16h. The mixture is cooled to 5-10°C and stirred for one hour. The solid was collected by filtration, mixed with water (200 mL) and ethyl acetate (500 mL). The mixture is adjusted to pH 10-12 with a 50% aqueous solution of sodium hydroxide to obtain two clear layers. The organic layer was separated and washed with water (200 ml), brine (200 ml) and dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was allowed to solidify and dried under vacuum at 20-25°C to give the title compound (57.2 g, 90%) as a white solid.

M.p. 72-74°C;

6H(300 MHz; CDCl3) 1.16(3H, t, J=7.6), 2.58(2H, q, J=7.6), 3.32(3H, s), 3.34(3H, s), 2.01-2.47(2H, m), 2.08-2.54(2H, m), 4.07-4.12(4H, m), 6.91(1H, d, J=7.6), 7.11(1H, s), 7.21(1H, t, J=7.8), 7.35(1H, s), 7.42(1H, s), 7.48(1H, d, J = 8.0), 8.13(1H, bs), 8.58(1H, s);

<SC (75.5 Mhz; CDC13) 15.4, 28.8, 59.1, 68.9, 70.4, 70.8, 103.0, 108.3, 109.3, 119.7, 121.7, 123.9, 128.8, 138.6, 145.1, 147.0, 148.6, 153.6, 154.4, 156.9;?max(KBr) cm<1>3136(s), 1624(s), 1575(s), 1487(s); m/z 398 (M+H)<+> (Found: C 65.64, H 6.96; N 10.32. C 22 H 27 N 3 O 4 O.25 H 2 O requires C 65.73, H 6.90; N 10.45).

Example 14

Preparation of N-(3-phenylphenyl)-6-(2-methoxyethoxy)-7-benzyloxy-4-quinazolinamine

N-(3-Ethylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine obtained as described above (4.0 g, 10 mmol), solid anhydrous sodium hydroxide (104 mg, 2.6 mmol) and benzyl alcohol (20 mL) were heated at 150-152°C for 23 hours. The reaction mixture was allowed to cool to room temperature and purified by column chromatography on silica gel using a gradient system with ethyl acetate/hexane as eluant to give a white solid which was dried under vacuum at 45-50°C to give the title compound (2.52 g, 58%)

M.p. 156-157°C;

5H(300 MHz; CDCl3) 1.17(3H, t, J=7.6), 2.58(2H, q, J=7.6), 3.32(3H, s), 3.33(3H, s), 3.65-3.68(2H, m), 4.07-4.11(2H, m), 5.11(2H, s), 6.93(1H, d, J=7.7), 7.18-7.29(5H, m), 7.35-7.42(4H, m), 7.50(1H, d, J = 8.0), 8.20(1H, bs), 8.61(1H, s), 5C(75.5 Mhz; CDC13) 14.2, 15.4, 28.8, 59.2, 69.2, 70.7, 70.8, 103.2, 109.1, 109.4, 119.7, 121.7, 124.0, 127.3, 128.1, 128.5, 128.8, 135.8, 138.6, 145.1, 147.0, 148.9, 153.7, 154.2, 156.9; ^ (KBr) cm1 1625, 1611, 1576; m/z430 (M+H)<+>(Found: C 71.42, H 6.50; N 9.48. C26H27N303 required C 72.70 H 6.34; N 9.78%).

Example 15

Preparation of N-(3-eUnylphenyl)-6-(2-methoxyethoxy)-7-butyloxy-4-quinazolinamine

N-(3-Ethylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine obtained as described above (4.0 g, 10 mmol), solid anhydrous sodium hydroxide (94 mg, 2.36 mmol) and butan-1-ol (20 mL) were heated at reflux for 12 days. The reaction mixture was allowed to cool to room temperature and purified by column chromatography on silica gel using a gradient system with ethyl acetate/hexane as eluent to give a white solid which was dried under vacuum at 45-50°C to give the title compound (2.57 g, mp 90-92°C).

5H(300 MHz; CDCl3) 0.93(3H, t, J 7.4), 1.19(3H, t, J=7.6), 1.45(2H, sextet, J 7.5), 1.79(2H, pentet, J6.9), 2.61(2H, q, J=7.6), 3.39(3H, s), 3.70-3.74(2H, m), 4.00(2H, t, J6.6), 4.12-4.15(2H, m), 6.94(1H, d, J=7.7), 7.15(1H, s), 7.24(1H, t, J=7.8), 7.34(1H, s), 7.44(1H, s), 7.51(1H, d, J=8.0), 7.95(1H, bs), 8.60(1H, s); 6C(75.5 Mhz; CDCl3) 13.8, 15.4, 28.8, 30.8, 59.3, 68.7, 69.3, 70.9, 103.2, 108.2, 108.9, 119.6, 121.4, 124.0, 128.9, 138.6, 145.2, 147.2, 148.8, 153.6, 154.9, 156.8; p^ s(KBr) cm"1 1618, 1576, 1519; m/z 396 (M+H)<+>

(Found: C 70.90, H 7.56; N 10.66. C 23 H 29 N 3 O 3 requires C 69.85, H 7.39; N 10.63%).

Example 16

Preparation of N-(4-methoxyphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine

4-Chloro-6,7-bis(2-methoxyethoxy)quinazoline (25g, 79.9mmol), 4-anisidine (9.8g, 79.9mmol) and propan-2-ol (250ml) were heated at 78-82°C for 16h. The mixture is cooled to 5-10°C and stirred for one hour. The solid was collected by filtration, and washed with propan-2-ol (25 mL). The isolated solid was recrystallized from an ethanol/water mixture that was dried in a vacuum oven overnight at 40-45°C. The recrystallized solid was mixed with water (100 mL) and ethyl acetate (250 mL). The mixture is adjusted to pH 10-12 with 50% aqueous sodium hydroxide solution to obtain two clear layers. The organic layer was separated and washed with water (200 ml), brine (200 ml) and dried over anhydrous magnesium sulfate, filtered and concentrated to give a white solid, then dried under vacuum at 40-45°C to give the product. 20.86 g, 65%, wt. 186-187°C.

<5H(300 MHz; CDCl3) 3.31(3H, s), 3.35(3H, s), 3.62-3.65(2H, m), 3.70-3.72(2H, m), 3.74(3H, s), 4.04-4.11(4H, m), 6.83(2H, d, J=9.0), 7.09(1H, s), 7.33(1H, s), 7.46(2H, d, J=9.0), 8.12(1H, bs), 8.58(1H, s); 5C(75.5 MHz; CDC13) 55.4, 68.2, 69.0, 70.4, 70.8, 103.1, 108.3, 109.1, 114.2, 124.7, 131.4, 146.8, 148.6, 153.7, 154.3, 156.7, 157.3; ymax (KBr) cm1 1619, 1590, 1582, 1511; m/z 400 (M+H)<+>(Found: C 63.30, H 6.37; N 10.47. C 21 H 25 N 3 O 5 requires C 63.30; H 6.31; N 10.52%).

Example 17

Obtaining N-(4-methoxyphenU)-6-(2-methoxyethoxy)-7-benzyloxy-4-quinazo

N-(4-Methoxyphenyl)-6,7-bis(2-methoxyethoxy)quinazolinamine, which was obtained as before (2g, 4.6mmol), solid anhydrous sodium hydroxide (104mg, 2.6mmol) and benzyl alcohol (20ml) were heated at 145-150°C for 18h. The reaction mixture was allowed to cool to room temperature and purified by column chromatography on silica gel using a gradient system with ethyl acetate/hexane as eluent to give a white solid which was dried under vacuum at 45-50°C to give the product. 0.915 g, 42%, wt. 208-209°C.

5H(300 MHz; €DC13) 3.34(3H, s), 3.91(2H, t, J=4.2), 3.74(3H, s), 4.10(2H, bs), 5.13(2H, s), 6.83(2H,.d, J=8.9), 7.20-7.30(5H, m), 7.36-7.38(3H, m), 7.47(2H, d, J=8.9), 8.10(1H, bs), 8.54(1H, s); 5C(75.5 MHz; CDCl3) 55.5, 59.3, 69.2, 70.7, 70.9, 103.3, 109.0, 109.1, 114.2, 124.6, 127.3, 128.1, 128.5, 131.3, 135.8, 146.8, 148.8, 153.7, 154.2, 154.2, 156.8, 157.2; vmex(KBr) cm1 1619, 1580, 1511; m/z 432 (M+H)<+>(Found: C 69.48, H 5.85; N 9.68 C 25 H 25 N 30 45 requires C 69.59; H 5.84; N 9.74%).

Example 18

Preparation of N-phenyl-N-methyl-6,7-bis(2-methoxyethoxy)-4-quinazolinamine

4-Chloro-6,7-bis(2-methoxyethoxy)quinazoline (10 g, 31.9 mmol), N-methylaniline (3.5 ml, 31.97 mmol) and acetonitrile (100 ml) were heated at 78-82°C for 24 hours. The mixture is cooled to 5-10°C and stirred for half an hour. The solid was collected by filtration, and dried for five hours in a vacuum oven at 50-55°C. The isolated solid was mixed with water (50 ml) and ethyl acetate (200 ml). The mixture is adjusted to pH 10-12 with 50% aqueous sodium hydroxide solution to obtain two clear layers. The organic layer was separated and washed with water (50 ml), brine (50 ml) and dried over anhydrous magnesium sulfate, filtered and concentrated to give a white solid, then dried under vacuum at 50-55°C to give the product. 8.55 g, 70%, wt. 109-111°C.

5H(300 MHz; CDCl3) 3.33(3H, s), 3.39(3H, s), 3.42-3.45(2H, m), 3.48-3.51(2H, m), 3.58(3H, s), 3.74-3.78(2H, m), 4.16-4.20(2H, m), 6.33(1H, s), 7.11-7.20(4H, m), 7.83(2H, t, J = 7.8), 8.68(1H, s); <5C(75.5 MHz; CDC13) 42.0, 59.2, 59.3, 67.6, 68.2, 70.3, 70.4, 106.5, 107.9, 110.9, 110.9, 125.8, 129.9, 147.0, 148.7, 153.0. N 10.96%).

Example 19

Preparation of N-phenyl-N-methyl-6-(2-methoxyethoxy)-7-butyloxy-4-quinazolinamine

N-methyl-N-phenyl-6,7-bis(2-methoxyethoxy)quinazolinamine obtained as described above (1.0 g, 2.61 mmol), solid anhydrous sodium hydroxide (97.5 mg, 2.43 mmol) and butan-l-ol (10 ml) were heated at reflux for 24 h. The reaction mixture was allowed to cool to room temperature and purified by column chromatography on silica gel using a gradient system with ethyl acetate/hexane as eluent to give a white solid which was dried under vacuum at 45-55°C to give the product 517 mg, 52%, wt. 62-62°C.

5H(300 MHz; CDCl3) 0.93(3H, t, J=7.4), 1.45(2H, sextet, J=7.4), 1.80(2H, pentet, J=6.7), 3.35(3H, s), 3.44-3.52(4H, m), 3.59(3.H, s), 4.05(2H, t, J=6.7), 4.05(2H, t, J=6.7), 6.34(1H, s), 7.12-7.21(4H, m), 7.34(2H, t, J=7.7), 8.69(1H, s); 6C(75.5 MHz; CDC13) 13.8, 19.2, 30.7, 42.0, 59.2, 67.8, 68.6, 70.4, 106.5, 107.7, 110.6, 125.8, 129.9, 147.0, 148.6, 153.0, 153.8, 160.4; vmdks(KBr) cm1 1616, 1572, 1543; m/z 382 (M+H)<+>(Found: C 69.39, H 7.38; N 10.86. C 22 H 27 N 3 O 3 requires C 69.27; H 7.14; N 11.02%).

Claims (13)

1. Procedure for obtaining compounds of Formula 1: or pharmaceutically acceptable salts or solvates thereof where: R<1> and R<2> are each independently selected from C1-C10alkyl and C1-C10alkoxy, where given alkyl and alkoxy are optionally substituted with up to two substituents independently selected from hydroxy and C1-C1alkoxy; R 15 is H, C 1 -C 10 alkyl or -CCH 2 ) q (C 6 -C 10 aryl), where q is a number from 0 to 4; characterized by comprising the reaction of a compound of Formula 2: where R<15>, R<1> and R<2><k> are as previously defined and G is a blocking group - C(OH)R<3>R<4>; R<3> and R<4> are each independently C1-C6 alkyl; with an alkali metal or alkali metal hydroxide in a solvent comprising a hydroxy substituted C 1 -C 10 alkyl. 2. The method according to claim 1, characterized in that the solvent is a secondary alcohol, and the alkali metal or alkali metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide. 3. The method according to claim 1, characterized in that the solvent is butan-2-ol or isopropanol or a mixture of two solvents and the given alkali metal or alkali metal hydroxide is sodium hydroxide. 4. The method according to claim 1, characterized in that R1 and R2 are 2-methoxyethoxy and R<15> is H. 5. The method according to claim 1, characterized in that the compound of formula 2 is obtained by the reaction of the compound of formula 3 where R<1> and R<2> are as defined in claim 1, with a compound of formula 4 wherein R 15 and G are as defined in claim 1. 6. The method according to claim 5, indicated by the fact that the compound of formula 3 is tertiated with the compound of formula 4 in an organic solvent selected from dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile and a mixture of two or more mentioned solvents. 7. The method according to claim 6, characterized in that the solvent is acetonitrile, and R<1> and R<2> are 2-methoxyethoxy, and R!s is H. 8. The method according to claim 5, characterized in that the compound of formula 3 is obtained by the reaction of the compound of formula 5 with thionyl chloride in anhydrous dichloromethane. 9. The method according to claim 8, characterized in that both R<1> and R<2> are 2-methoxyethoxy. 10. Process for obtaining compounds of formula 6 or 7 or Pharmaceutically acceptable salts or solvates thereof, where R<6>,C(-C 10 alkyl or -(CH2)mO(CH2)nCH3; R<7>is Ci-Cioalkyl or (Ci-C6alkyl)(C6-Ci0aryl) where the R<7> groups are optionally substituted with 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, trifluoromethoxy, (Ci-C6alkyl)sulfonyl, Ci-C6alkyl, C1-C6alkyloxy, C6-Cioaryloxy and C6-Cioarylsulfonyl; each m is independently a number from 1 to 6 and n is a number from 0 to 3; R15 is H, C1-C10alkyl or -(CH2)q(C6-C10aryl) where q is a number from 0 to 4; characterized by the fact that it includes the reaction of compounds of the formula 8 wherein R<6> and R<15> are as previously defined, G' is -C(OH)R<3>R<4> and R<3> and R<4> are each independently C1C6alkyl; with a primary alcohol of the formula R<7->OH where R<7> is CrCi0alkyl or -(Ci-C6alkylKCe-Cioaryl), and given R<7> groups are optionally substituted with 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, trifluoromethoxy, (Ci-C6alkyl)sulfonyl, C1-C6alkyl, C1-C6alkyloxy, C6-Cioaryloxy and C6-Cioarylsulfonyl; in the presence of alkali metal or alkali metal hydroxide. 11. The method according to claim 10, characterized in that the given alkali metal or alkali metal hydroxide is selected from the group consisting of sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide. 12. The method according to claim 11, characterized in that the given alkali metal or alkali metal hydroxide is sodium hydroxide, R6 is 2-methoxyethoxy, R15 is H and the alcohol of the formula R<7->OH is a secondary alcohol. 13. Compound of formula 2 gde su R<l>i R<2>nezavisno odabrani od Ci-Cioalkil i Ci-doalkoksi, gde su dati alkil i alkoksi po potrebi supstituisani sa do2 supstituenta nezavisno odabrana od hidroksi iC\-Cćalkoksi; G is a blocking group -C(OH)R3R4; R<3> and R<4> are each independently C1-C6alkyl; and R<iS>is H, C1-C10alkyl or -CCH2)q(C6-C10aryl), where q is a number from 0 to 4.